The outcome of a viral infection is the result of a complex interplay between host and viral components. Although the majority of humans show either no clinical symptoms or febrile disease after WNV infection, about 10 to 20% develop severe disease which is sometimes fatal. The elderly are at greater risk for developing disease, but individuals of different ages and without obvious immunodeficiency are represented in the disease population suggesting that a genetic component may be involved in conferring an increased predisposition to disease. Horse populations show a similar response to WNV infection. In mice, a single gene (FIv) alters both the level of flavivirus production and disease outcome. This gene was recently identified by our lab as one of eight 2'-5' oligoadenylate synthetase (Oas)1 genes (Perelygin et al., 2002). Oas genes are part of the innate immune system but the mechanism by which the mouse gene functions is not known. Preliminary data from TBEV-infected humans suggest an association between particular polymorphisms in the OAS gene cluster and disease response. We propose to identify human and horse genes associated with predisposition to severe flavivirus-induced disease using screening of selected polymorphisms in the OAS genes and, if necessary, in other genes in the OAS gene activity pathways in WNV-infected individuals with various responses to infection. Associations between disease susceptibility and particular polymorphisms will be determined statistically. Haplotype blocks will be first identified as a prelude and guide to these analyses. The haplotypes within each block will then be determined, and their frequencies will be compared between the different response groups. Further analyses will include fine mapping and sequencing of the causative mutation(s).